NM_004698.4:c.-48-5_-48-3dupTTT

Variant names:

• chr1-150324880-C-CTTT
• rs75011188
• NM_004698.4:c.-48-5_-48-3dupTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BA1

The NM_004698.4(PRPF3):​c.-48-5_-48-3dupTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1901 hom., cov: 0)
  • Exomes 𝑓: 0.36 (9793 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRPF3 NM_004698.4 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.713
• Publications: 0 publications found

Genes affected

PRPF3 (HGNC:17348): (pre-mRNA processing factor 3) The removal of introns from nuclear pre-mRNAs occurs on complexes called spliceosomes, which are made up of 4 small nuclear ribonucleoprotein (snRNP) particles and an undefined number of transiently associated splicing factors. This gene product is one of several proteins that associate with U4 and U6 snRNPs. Mutations in this gene are associated with retinitis pigmentosa-18. [provided by RefSeq, Jul 2008]

PRPF3 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09405458 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: ctctttttttttttttttAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 1-150324880-C-CTTT is Benign according to our data. Variant chr1-150324880-C-CTTT is described in ClinVar as Benign. ClinVar VariationId is 1178706.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004698.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF3	NM_004698.4	MANE Select	c.-48-5_-48-3dupTTT		splice_acceptor intron	N/A	NP_004689.1	O43395-1
	PRPF3	NM_001350529.1		c.-549-5_-549-3dupTTT		splice_acceptor intron	N/A	NP_001337458.1
	PRPF3	NR_146766.1		n.126-5_126-3dupTTT		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF3	ENST00000324862.7	TSL:1 MANE Select	c.-48-15_-48-14insTTT		intron	N/A	ENSP00000315379.6	O43395-1
	PRPF3	ENST00000496202.5	TSL:1	n.115-15_115-14insTTT		intron	N/A
	PRPF3	ENST00000907626.1		c.-48-15_-48-14insTTT		intron	N/A	ENSP00000577685.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 20814 AN: 144042 Hom.: 1900 Cov.: 0

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.143

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.357 AC: 419749 AN: 1176664 Hom.: 9793 Cov.: 24 AF XY: 0.356 AC XY: 210468 AN XY: 591106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.333 AC: 8272 AN: 24840

American (AMR) AF: 0.335 AC: 10275 AN: 30628

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 6746 AN: 20128

East Asian (EAS) AF: 0.362 AC: 11642 AN: 32146

South Asian (SAS) AF: 0.334 AC: 24017 AN: 71860

European-Finnish (FIN) AF: 0.354 AC: 12880 AN: 36336

Middle Eastern (MID) AF: 0.372 AC: 1312 AN: 3524

European-Non Finnish (NFE) AF: 0.360 AC: 328026 AN: 909984

Other (OTH) AF: 0.351 AC: 16579 AN: 47218

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.145 AC: 20818 AN: 144068 Hom.: 1901 Cov.: 0 AF XY: 0.145 AC XY: 10078 AN XY: 69582

African (AFR) AF: 0.0376 AC: 1472 AN: 39118

American (AMR) AF: 0.126 AC: 1806 AN: 14358

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 665 AN: 3422

East Asian (EAS) AF: 0.222 AC: 1115 AN: 5032

South Asian (SAS) AF: 0.150 AC: 690 AN: 4614

European-Finnish (FIN) AF: 0.190 AC: 1515 AN: 7956

Middle Eastern (MID) AF: 0.121 AC: 34 AN: 282

European-Non Finnish (NFE) AF: 0.197 AC: 13055 AN: 66392

Other (OTH) AF: 0.142 AC: 283 AN: 1990

Alfa AF: 0.152 Hom.: 1622

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75011188; hg19: chr1-150297334;